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\Environmental Health Perspectives (EHP) is a monthly peer-reviewed journal of research and news published with support from the National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services. The mission of EHP is to serve as a forum for the discussion of the interrelationships between the environment and human health by publishing high-quality research and news of the field. With an impact factor of 7.03, EHP is the third-ranked journal in Public, Environmental, and Occupational Health, the fourth-ranked journal in Toxicology, and the fifth-ranked journal in Environmental Sciences

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Abstract

Carcinogenic effects of chemical mixtures were examined with a medium-term liver bioassay for carcinogens or a multiorgan medium-term bioassay using male F344 rats. In the medium-term liver bioassay, rats were initially treated with diethylnitrosamine (DEN) at 200 mg/kg body weight, ip; after 2 weeks they received chemical mixtures such as 10 different heterocyclic amines at one-tenth or one-hundredth the dose levels used in carcinogenicity studies and the mixtures of 20 different pesticides, each at acceptable daily intake (ADI) levels or a mixture of 100 times ADI levels. All animals were subjected to two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. The numbers and areas of glutathione S-transferase placental form (GST-P) positive foci (preneoplastic lesions in the liver) were compared between respective groups. When 10 heterocyclic amines were mixed in the diet at one-tenth dose level, clear synergism was observed, but no combined effects were evident with the one-hundredth dose levels. In the pesticide experiment, treatment of rats with the 20-pesticide mixture at the ADI dose level did not enhance GST-P-positive foci. In contrast, a mixture of 100 times the ADI significantly increased those values. In a multiorgan bioassay of 28 weeks, mixtures of 40 high-volume compounds and 20 pesticides (suspected carcinogens) added together at their respective ADI levels did not enhance carcinogenesis in any organs initiated by five different carcinogens (DEN, N-methylnitrosourea, dimethylhydrazine, N-butyl-N-(4-hydroxybutyl)nitrosamine, and dihydroxy-din-propylnitrosamine) in combination. The combination effect of low dietary levels of five antioxidants, butylated hydroxyanisole, caffeic acid, sesamol, 4-methoxyphenol, and catechol, were also examined using the multiorgan bioassay. The incidence of forestomach papillomas was significantly increased only in the combination group and the results indicate that combination of the five antioxidants can exert additive/synergistic effects on tumorigenesis in the multiorgan bioassay. These results indicate that chemical mixtures at very low doses did not enhance preneoplastic lesions synergistically but the mixtures at certain doses show synergism in the target organ. The medium-term bioassays are particularly useful tools for this purpose.